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Role of BRCA Mutations in Advanced Ovarian Cancer

Insights From: Michael Birrer, MD, ONeal Comprehensive Cancer Center; Ursula A. Matulonis, MD, Dana-Farber Cancer Institute; Kathleen Moore, MD, Stephenson Cancer Center
Published: Monday, Apr 29, 2019



Transcript: 

Kathleen Moore, MD:
Identification of germline mutations, such as BRCA1 or BRCA2, is basically essential in epithelial ovarian cancer. It’s a must-do. Patients can decline testing, but all patients should be offered. So really the most important message is that there’s no selection for who gets offered testing and hopefully who’s tested. Everyone should be tested.

And, why is that? No 1, if we identify patients who have a germline mutation in BRCA1 or BRCA2, which is about 17% to 18% of high-grade serous and high-grade endometrioid, depending on the population, it does give us prognostic information. So we do know from epidemiological studies that women who have a BRCA mutation or BRCA-related ovarian cancer didn’t have a longer survival owing in large part to the increased sensitivity to chemotherapy, especially DNA-damaging chemotherapies that having a BRCA mutation bring. So the BRCA mutation, unfortunately, led to the development of the ovarian cancer but also can be kind of an Achilles’ heel for the cancer in terms of its response to chemotherapy.

It gives us information about prognosis. It gives us the opportunity to offer testing to first-degree relatives. This is called cascade testing. If you have a patient with a known BRCA germline mutation, then her brothers and sisters—it’s not a sex-linked mutation—both men and women can be a carrier at the 50% passed-down rate with each generation. So all their siblings should be offered testing. And if they test negative, then their children are not at risk. But if they test positive, then you have the opportunity when their children come of age to offer them testing as well.

And if you identify subsequent mutation carriers before they get cancer, you can create what some would term “previvors,” where you can do things that aren’t small. You can do risk-reducing surgeries to prevent breast cancer, to prevent the ovarian cancer from developing in men with BRCA2 or to prevent breast cancer. There’s different surveillance for BRCA2, and there are risks with pancreas cancer, for example. So there are high-risk clinics that these patients can be referred to. We try to prevent them from becoming our patients, which is really the ultimate goal. So cascade testing is critical. We don’t do a great job of it in this country.

And the third thing to know is that it’s a predictive biomarker for response to DNA-damaging therapies such as carboplatin but, more importantly, now agents such as PARP inhibitors. And there are several other assets in the pipeline that may come to availability as well that these patients will derive benefit from. So if we identify these patients, we know that they will benefit from a PARP inhibitor, and they need a PARP inhibitor with frontline therapy. So some knowledge of germline is incredibly important.

Maybe it’s a little more, but right now we think there are about 7% of patients who—if you test their tumor—they have a deleterious BRCA1 or BRCA2 mutation as well. So they have no genetic predisposition, and they’re not at risk of passing on anything to children, but their tumor looks as if it has a BRCA mutation. And the importance there is, again, the predictive biomarker and potential of that. Findings show that they also respond just as well to PARP inhibitor use as germline patients. And so they derive all that benefit as well, so we want to make sure we identify those patients, so we don’t deny them the opportunity to access a very effective therapy.


Transcript Edited for Clarity 
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Transcript: 

Kathleen Moore, MD:
Identification of germline mutations, such as BRCA1 or BRCA2, is basically essential in epithelial ovarian cancer. It’s a must-do. Patients can decline testing, but all patients should be offered. So really the most important message is that there’s no selection for who gets offered testing and hopefully who’s tested. Everyone should be tested.

And, why is that? No 1, if we identify patients who have a germline mutation in BRCA1 or BRCA2, which is about 17% to 18% of high-grade serous and high-grade endometrioid, depending on the population, it does give us prognostic information. So we do know from epidemiological studies that women who have a BRCA mutation or BRCA-related ovarian cancer didn’t have a longer survival owing in large part to the increased sensitivity to chemotherapy, especially DNA-damaging chemotherapies that having a BRCA mutation bring. So the BRCA mutation, unfortunately, led to the development of the ovarian cancer but also can be kind of an Achilles’ heel for the cancer in terms of its response to chemotherapy.

It gives us information about prognosis. It gives us the opportunity to offer testing to first-degree relatives. This is called cascade testing. If you have a patient with a known BRCA germline mutation, then her brothers and sisters—it’s not a sex-linked mutation—both men and women can be a carrier at the 50% passed-down rate with each generation. So all their siblings should be offered testing. And if they test negative, then their children are not at risk. But if they test positive, then you have the opportunity when their children come of age to offer them testing as well.

And if you identify subsequent mutation carriers before they get cancer, you can create what some would term “previvors,” where you can do things that aren’t small. You can do risk-reducing surgeries to prevent breast cancer, to prevent the ovarian cancer from developing in men with BRCA2 or to prevent breast cancer. There’s different surveillance for BRCA2, and there are risks with pancreas cancer, for example. So there are high-risk clinics that these patients can be referred to. We try to prevent them from becoming our patients, which is really the ultimate goal. So cascade testing is critical. We don’t do a great job of it in this country.

And the third thing to know is that it’s a predictive biomarker for response to DNA-damaging therapies such as carboplatin but, more importantly, now agents such as PARP inhibitors. And there are several other assets in the pipeline that may come to availability as well that these patients will derive benefit from. So if we identify these patients, we know that they will benefit from a PARP inhibitor, and they need a PARP inhibitor with frontline therapy. So some knowledge of germline is incredibly important.

Maybe it’s a little more, but right now we think there are about 7% of patients who—if you test their tumor—they have a deleterious BRCA1 or BRCA2 mutation as well. So they have no genetic predisposition, and they’re not at risk of passing on anything to children, but their tumor looks as if it has a BRCA mutation. And the importance there is, again, the predictive biomarker and potential of that. Findings show that they also respond just as well to PARP inhibitor use as germline patients. And so they derive all that benefit as well, so we want to make sure we identify those patients, so we don’t deny them the opportunity to access a very effective therapy.


Transcript Edited for Clarity 
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